Myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Fibromyalgia syndrome (FM) are chronic multi-symptom disorders, which are frequently comorbid. The primary goal of this study is to identify unique genetic mutations seen in ME/CFS and/or FM but not in depression or other functional disorders like migraine. Identifying such variants would provide specific biomarkers for diagnosis of ME/CFS and FM and for identifying causes and targets for treatment. Both ME/CFS and FM have been proposed to involve mitochondrial dysfunction. Recently, we employed RNA-Seq and VarScan2 to examine mutations in leukocytes (not whole blood) for the full human transcriptome. In a pilot sample, 94% of the 17 ME/CFS patients had High or Moderate Impact variants in mitochondrial genes affecting NADH dehdrogenase 4, and the 17th had mitochondrial variants affecting cytochrome B. Both are proteins in the respiratory chain complexes that have critical roles in production of ATP, the cell's major energy source. Known mitochondrial disorders are associated with other mutations affecting these same complexes. Like ME/CFS, these mitochondrial disorders involve symptoms of muscle weakness, fatigue, neuropathies and exercise intolerance. Most of our 17 patients also had a second mitochondrial variant affecting ATP production and also a chromosomal DNA variant affecting either mitochondrial replication or autoimmune function. Thus, we hypothesize that mutations in mitochondrial genes (especially in combination with other mutations) increase risk or contribute causally to the development of ME/CFS and/or FM, and may be specific biomarkers of these disorders. Specific aims of the study are: First, to use RNA-Seq and VarScan2 to compare the frequency of leukocyte mitochondrial mutations of 150 patients with ME/CFS and/or FM versus 150 healthy controls, patients with migraines or depression (total sample= 300). Second, to examine the relationship between greater heteroplasmy of these mutations and severity of physical fatigue, mental fog and widespread pain in all 150 CFS/ME and FM patients. Third, in mothers of 40 ME/CFS or FM patients with mitochondrial mutations, to assess whether they share their child's mutation, indicating what proportion of patients have maternally inherited vs. acquired somatic mutations.